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With four targeted therapy drugs now approved by the U.S. Food and Drug Administration to treat patients with advanced HER2-positive breast cancers—lapatinib, trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1)—the American Society of Clinical Oncology's two new clinical practice guidelines on treating women with advanced HER2-positive breast cancer are very timely. The guidelines, “Systemic Therapy for Patients with Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer” and “Recommendations on Disease Management for Patients with Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases,” are now available online ahead of print in the Journal of Clinical Oncology (citations below).

“We have several treatments for advanced HER2-positive breast cancer, all of which are associated with improved survival,” Eric P. Winer, MD, Co-chair of ASCO's Expert Panel that developed the guidelines, said in a news release. “We're very fortunate that now we have multiple studies that give us a clear picture of how these newer agents should be used.”

The practice guideline on systemic therapy for patients with HER2-positive breast cancer (doi: 10.1200/JCO.2013.54.0948) is based on a formal, systematic review of relevant medical literature that identified 19 randomized Phase III clinical trials on HER2-targeted therapies.

Based on the review, the following recommendations were made for first, second, and third lines of therapy:

* First-line therapy: Use a combination of chemotherapy, trastuzumab, and pertuzumab. For select patients, such as those with contraindications and/or slow-growing hormone receptor-positive cancer, hormonal therapy administered with or without either trastuzumab or lapatinib may be substituted for a chemotherapy-based HER2-targeted regimen because it may have fewer side effects. However, hormonal therapy is not appropriate for all patients with advanced, HR-positive breast cancer, and it has not been associated with a survival benefit in this setting.

* Second-line therapy: T-DM1

* Third-line line therapy and beyond: Treatment depends on what patients have received in the first- and second-lines. Options may include T-DM1, hormonal therapy or chemotherapy with trastuzumab and in some cases with lapatinib, the combination of trastuzumab and lapatinib, or a pertuzumab-based regimen if the patient had not previously received pertuzumab.

For Treating Brain Metastases, Only Limited Data Available

The practice guideline for treating brain metastases in patients with HER2-positive breast cancer (doi: 10.1200/JCO.2013.54.0955) was developed because there are limited data on treating brain metastases in this population and no systemic treatments are specifically approved, the authors said. There was input from neurosurgeons and radiation oncologists as well as medical oncologists, and includes surgery, radiotherapy, and systemic therapies as options as well as for best supportive care, enrollment in a clinical trial, and/or palliative care.

In a telephone interview, Winer, Chief of the Division of Women's Cancers and Director of the Breast Oncology Center at Dana-Farber Cancer Institute, called the guidelines not so much practice changing as “practice defining—meaning that they help oncologists sort through what is and is not reasonable.”

“There are already many oncologists who practice this way,” he said. “It's the way I and many of my colleagues practice—but we know that not everyone across the U.S. practices the same way, or has to practice the same way. Guidelines are a way of organizing how we think about data.”

The guidelines for medical therapy categorizes each recommendation as evidence based or as the result of informal consensus; rates the evidence quality as high, intermediate, or insufficient; and rates the strength of the recommendation as strong, moderate, or weak.

Winer said that regardless of a “weak” characterization, those recommendations wouldn't have been made if the panel had not felt some justification for it.

“The oncologist who doesn't have a strong feeling to the contrary should go with that recommendation,” he said. “But that being said, if this is a situation where an oncologist has some alternative to consider or a strong reason not to go with that recommendation, then it is reasonable to bring your own thoughts and judgments into it.

“And of course in any situation, there are always exceptional patients who should not be treated according to standard guidelines,” Winer continued. “Guidelines only work for the majority of patients—they don't pretend to cover 100 percent of all patients.”

The panel's other co-chair, Sharon Giordano, MD, MPH, Chair of the Department of Health Services Research and Professor of Medicine in the Department of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center, said that in areas where there is low strength for the recommendation, there is more flexibility for how the practitioner chooses to treat the patient.

“These areas are often the most controversial and difficult because we don't have strong evidence behind them—that's why we thought it would still be useful to provide some guidance about how these patients should be treated,” she said in an interview. “This can give clinicians confidence that they are doing what most people consider appropriate for most patients.”

Another case where more of the decision is left up to the clinician is the patient who has HER-2 positive disease but is treated with endocrine therapy alone (if the patient has ER-positive or PgR-positive disease).

Such patients, Winer said, might be so selected because of cardiac disease, indolent breast cancer, or other reasons. “We actually left it open to the doctor to decide when to recommend endocrine therapy alone. We did not feel we had evidence to suggest that it was inappropriate in at least some subset of patient to use endocrine therapy alone. We recognize that is a very small subset of patients—typically those who appear to have very indolent disease, and some of those patients may stay on endocrine therapy for many months before needing any intravenous therapy.

“But that is the rare patient,” he emphasized. “In my own clinical practice that comes up very, very rarely.”

The Expert Panel for the brain metastases guideline developed the guideline recommendations using an expert consensus process, supplemented by a Consensus Ratings Panel.

Winer said the recommendations regarding brain metastases are very relevant to medical oncologists. Even if initial treatment for the metastases is typically surgery or radiation, ultimately many of those patients have disease progression and will be treated with a variety of systemic therapies.

“While we were not able to be terribly specific about what therapies could be offered [the patient with brain metastases], we suggested some,” he said. “This is very relevant to the medical oncologist because the medical oncologist is really functioning as the primary cancer care giver here, and is going to have to guide the patient.”

Key Recommendations

* For patients with favorable prognosis for survival, surgery and/or radiotherapy are recommended, depending on the size and number of metastases, resectability, and symptoms.

* For patients with a poor prognosis for survival, options include surgery, whole-brain radiation therapy, and systemic therapies with some evidence of activity in the setting of brain metastases, such as lapatinib and capecitabine.

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